Aryloxyacetates of basically substituted arylakanols and derivatives thereof



Patented Feb. 17, 1953 UNITED STATES PATENT OFFICE ARYLOXYACETATES OF BASICALLY SUB- STITUTED ARYLALKANOLS AND DE- RIVATIVES THEREOF John W. Cusic, Skokie, Ill., assignor to G.'D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application February 24, 1951, Serial No. 212,679

Claims.

wherein Ar and Ar are aromatic radicals and NRR' is a member of the class comprising dialkylamino radicals and nitrogen-containing heteromonocyclic radicals attached to the alkylene radical through a nitrogen in the heteromonocycle and salts thereof.

In the foregoing structural formula, Ar and Ar represent such aromatic radicals as phenyl, tolyl, naphthyl, fiuorenyl, phenanthryl and substitution products thereof such as the halogen and methoxy derivatives. The alkylene radical represents bivalent, saturated, aliphatic hydrocarbon radicals of from two to eight carbon atoms. These radicals are derived from straight-chain and branched-chain aliphatic hydrocarbons and include radicals such as ethylene, propylene, butylene, amylene and polymethylene radicals such as trimethylene, tetramethylene, pentamethylene and hexamethylene.

Among the radicals which R and R may represent are such lower alkyl groups as methyl, ethyl, propyl, butyl, amyl, and hexyl, wherein the propyl, butyl, amyl, and hexyl groups may be either of the straight-chain or branched-chain type. The radical NRR' may also be a nitrogencontaining heteromonocyclic radical such as N- piperidino, N-lupetidino, N-pyrrolidino, N-morpholino, N-thiamorpholino, N-piperazino, N'-alkyl-N-piperazino and the like.

The organic bases of the foregoing type form salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate, diethyl sulfate, methyl benzene sulfonate, ethyl toluene sulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The above esters are conveniently prepared by heating an aryloxyacetyl halide with a corresponding alcohol of the type wherein all symbols are defined as hereinabove, under anhydrous conditions in an inert solvent such as a lower aromatic hydrocarbon.

The esters of this invention are valuable intermediates in organic synthesis. They have been found to possess useful pharmacodynamic properties upon the renal excretory system, and to have particular utility as diuretic agents.

My invention will be described more fully in conjunction with the following examples. It will be understood, however, that these examples are given by Way of illustration only, and that the invention is not to be construed as limited in spirit or in scope by the details set forth. It will be apparent to chemists skilled in the art of organic synthesis that many modifications in materials, conditions and methods may be made without departing from the invention. In each of these examples, temperatures are given uncorrected in degrees centig'rade (C.), amounts of materials in parts by weight, and pressures durin vacuum distillation in millimeters (mm) of mercury.

EXAMPLE 1 Phcnoxyacetcte of a-dtethylaminomethylbenzyl alcohol A mixture of parts of phenoxyacetyl chloride and a-diethylaminomethylbenzyl alcohol in 2600 parts of benzene is heated at refluxing temperature for fifteen hours with constant agitation. Upon cooling a precipitate forms. The mixture is treated with dilute, aqueous hydrochloric acid. The aqueous layer is separated and rendered alkaline by addition of sodium hydroxide. The base is extracted with ether, and the ether extract is dried over anhydrous potassium carbonate, filter-ed, and evaporated. The phenoxyacetate of a-diethylaminomethylbenzyl alcohol is distilled at 1 mm. pressure and about -l88 C. An ether solution of the base is treated with a 25% solution of hydrogen chloride in anhydrous isopropanol. The crystalline hydrochloride solidifies readily. Recrystallized from isopropanol, it melts at about 127-129 C. The base has the structural formula EXAMPLE 2 o-C'hlorophenoxyacetate of a-dz'ethylaminomethylbenzyl alcohol ylaminomethylbenzyl alcohol is distilled at 2 mm.

pressure and about 205 C.

EXAMPLE 3 9,1 -Dicltlcrophenoxyacetate of a-dz'ethyZam-inomcthylbcnzyl alcohol A mixture of 239 parts of o,p-dichlorophenoxyacetic acid and 193 parts of a-diethylaminomethyl benzyl alcohol and 2600 parts of benzene is stirred and heated at refluxing temperature for fifteen hours. The resulting solution is treated with aqueous hydrochloric acid. The aqueous layer is separated and the base liberated by treatment with pota sium hydroxide. The extracted with ether and the extract dried over anhydrous potassium carbonate, filtered, and evaporated. The o,p-dichlorophenoxyacetate oi" m-diethylaminon'iethylbenzyl alcohol boils at 2l- 216 C. at 2 mm. pressure. An ether solution of this compound is treated with an equivalent of alcoholic hydrogen chloride. The hydrochloride precipitates upon standing at C. Recrystallization from isopropanol yields crystals melting at about 151-153" C.

EXAldPLE 4 o .p-DichZorophenoryacetate of (c-hg dromy-fiphcncthyl) diethZ/Zmethylammonium iodide A solution of 100 parts of o,p-dichlorophenoxyacetate of a-diethylaminomethylbenzyl alcohol and 166 parts of methyl iodide in 400 parts 01' butanone is stirred at 6 C. for twelve hours. Addition of a small amount of ether causes separation of oily precipitate which solidifies on standing at 0 C. for several days. It is collected on a filter and warmed with butanone to dissolve the oil. Upon cooling and storage at 0 C., a precipitate forms which is collected on a filter. The o,p-dichlorophenoxyacetate of (B-hydroxye phenethyl)diethylmethylammonium iodide melts at about l31-l33 C. and has the structural formula EXAMPLE o-An-z'syloryacetate of a-(2-phenanthrg Z)-4- morpholmcpropanol A ixture of 261 parts of o-methoxyphenoxyacetyl chloride and 321 parts of a-(Z-p-henanthryl) lnnorpholinepropanol (cf. E. Mosettig, et al. J. A. C. S. 60, 246%; 1938) in 4590 parts of benzene is stirred and heated at refluxing temperature for fifteen hours. The mixture-is then treated with aqueous hydrochloric acid, the aqueone layer separated, rendered alkaline by addibase is tion of dilute ammonium hydroxide, and extracted with ether. The extract is dried over anhydrous potassium carbonate, stirred with decolorizing charcoal and filtered. Evaporation of the filtrate yields the o-anisyloxyacetate of (2-phenanthryl) -4-morpho1inepropanol as a light yellow oil. This compound has the structural formula OCH:

OH-CHz-CHz-N EXAMPLE 6 B-Naphthoxyacetate of a(3,4-methylenedioa:yphenz/Z) -1 -piperidinebutanol 2'77 parts of a-(3,4-methylenedioxyphenyl) -1- piperidinebutanol, prepared by the method of A. Marxer (Helv. Chim. A., 24; 2393; 1941) are heated at refluxing temperature with 221 parts of 2-naphthoxyacetyl chloride in 5600 parts of benzene with constant agitation for twelve hours.

After cooling, the reaction mixture is treated with aqueous hydrochloric acid and the aqueous layer made alkaline by addition of dilute potassium hydroxide and extracted with ether. The extract is dried over anhydrous potassium carbonate and filtered with the use of charcoal as a clarifying agent. Upon evaporation, the base is obtained as a light-colored oil. To prepare the methobromide, 1% parts of this base are heated for two hours with parts of methyl bromide in 460 parts of butanone in a shielded pressure vessel. After cooling and treatment with ether, an oil. separates which solidifies upon storage at 0" C. It has the structural formula I claim:

1. The group of organic compounds consisting of the aryloxyacetates of basically substituted arylalkanols of the structural formula and salts thereof, wherein Ar and Ar are members of the class consisting of aryl hydrocarbon radicals containing 6' to 12 carbon atoms, their lower alkoxy derivatives and halogenated derivatives, Alk is a lower alkylene radical and. NRR is a member of the class consisting of lower dialkylamino, morpholino, pyrrolidino and piperidino radicals.

2. The aryloxyacetates of N,N-d.ialkyl-o-aryiw-hydroxyalkylamines of the structural formula Ar-O-CH2-COO-CH (A1" Alk-N (lower allryl) 2 wherein Ar and Ar are aryl hydrocarbon radicals containing 6 to 12 carbon atoms and Alk is a lower alkylene radical.

3. The phenoxyacetates of N,N dialkyl-wphenyl-w'-hydroxyalkylamines of the structural formula CsH5-O-CH2-COO-CH(C&H5) -A1l N (lower alkyl) wherein Alk is a lower alkylene radical.

The pheuczyaeetate of ct-rtliethylamineethylbenzyl alcohol.

The halogenated ar,,'l :ya "tates of Nil-clii-w-&l"/1w-hyl s of the ssruetural formula Ar-O-CE1z-COO-C wherein Ar is taming 6 to clrecaroen r halogenategl aryl. radical "om at L I *7 s an aryl hyl 12 carbon atoms ates of N--;li .roxyar of the struca]kyl-wphenyl-e-h tural formula ,lu -d1alkylt: e structural whenylw -hydroxyalkylai formula wherein All; i a lower all' lene radieal.

The c oro moxyaeetates of hel. alcohol.

9. The clichlorcphenoxyacetates of I cliallzylw-phenyl-w-hydrxyalkyla of the structural formula wherein All: is a lower alkyl 18. The Qp-diohlorophm ylaminomethylbensyl ale 11. The aryloxyacet 1 triall'ylwaryl-w-hyclroxyalkyl)ammonium salt of the structural formula Ar-OCH2C O O-CH(Ar)-A1kN (lower alkyl);

wherein Ar and Ar are aryl hydrocarbon radicals containing 6 to 12 carbon atoms, All: is a lower alkylene radical and X is one equivalent of an anion.

wherein Ar is a halogenated aryl radical con taining 6 to 12 carbon atoms, Ar is an aryl hydrocarbon radical containing 6 to 12 carbon atoms, All: is a lower alkylene radical and X is one equivalent of an anion.

14. The chlorinated phenoxyacetates of B-hyclroxy-fi-phenethyl)trialkylammonium salts of the structural formula -O-CH2OO 0-CH(CeH5)-OH2I(1ower alkyDx wherein X is one equivalent of an anion and n is an integer smaller than 3.

15. The o,p-dichlorophenoxyacetates sf (lihyclroxy e phenetliyl) tiiethylmethylammonium halides.

JOHN VJ. CUSIC,

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,372,116 Pierce et al. Mar. 3794: 2,415,235 Christiansen et al. Feb 4, 194'? 2,428,978 Martin et a1. Oct. 14, 19%? OTHER REFERENCES McElvain et al.: Chem. Abstracts, vol. 41, col. 2047 (1947). 

1. THE GROUP OF ORGANIC COMPOUNDS CONSISTING OF THE ARYLOXYACETATES OF BASICALLY SUBSTITUTED ARYLALKANOLS OF THE STRUCTURAL FORMULA 